Project 1 (P1). Abstract Myeloperoxidase (MPO) is an oxidant-generating leukocyte-derived enzyme with numerous mechanistic links to cardiovascular disease (CVD). Paraoxonase 1 (PON1) is an HDL-associated protein that promotes systemic anti-oxidant effects and is athero-protective. We have recently shown that MPO, PON1 and HDL can form a functional ternary complex, influencing each other?s activity. The present proposal is a continuation of these findings, and seeks to examine whether MPO and PON1 reciprocally influence each other?s activity in the artery wall during the development of atherosclerotic CVD, as well as during adverse ventricular remodeling and heart failure (HF) development following myocardial infarction (MI). It integrates studies on genetics, structure and function of proteins involved in inflammation and oxidation pathways operative in animal models of disease, and human clinical studies involving CVD and HF risk. Our overall goals are to test the hypotheses that MPO and PON1 functionally impact each other?s activity during different stages of CVD, and to leverage this understanding for development of improved CVD-targeted diagnostics and therapeutics. We will do so through the following Specific Aims: Aim 1) We will test the hypothesis that genetic determinants of PON1 functionally impact MPO activity within the artery wall influencing atherosclerosis, and within ventricular tissues following MI, impacting remodeling and HF risk. Aim 2) We will test whether specific post-translational modifications to PON1 formed by MPO within human atheroma impair PON1 function in vitro and in vivo, and whether PON1 can serve as a therapeutic agent in the post MI setting. The proposed studies employ multidisciplinary and translational research approaches. Successful completion of these studies will help discover key genetic, structural and functional relationships linking MPO and PON1 with one another and with risks for development of CVD and HF. They also will help develop and validate new diagnostic tests for heart disease risk prediction, and potential novel CVD-targeted therapeutics.